Role of lymphocytes and newly discovered cochlear lymphatics in the foreign body response following cochlear implantation

项目摘要 耳蜗植入物（CI）为重度至极重度感觉神经性耳聋患者提供听觉康复。 听力损失，现在可以使具有显著残余低频听力的患者受益。植入物功能和 残余听力可能受到CI后炎性异物反应（FBR）的负面影响。而 大量的工作致力于探索浸润性巨噬细胞的作用，淋巴细胞的作用 还没有被彻底审查。此外，抗原呈递细胞（APC，例如，巨噬细胞）已知 从终末器官通过淋巴管网络向淋巴结移动，将抗原呈递给淋巴细胞， 激活并募集淋巴细胞。耳蜗淋巴网络从未被描述过。使用淋巴管 报告小鼠和高灵敏度和特异性的淋巴管示踪分子，我们已经发现了一个 耳蜗内有丰富的淋巴网络。此外，在小鼠CI模型中，我们观察到淋巴细胞浸润 和激活强化人类研究中的发现。鉴于淋巴解剖学的潜在重要性， 淋巴细胞在耳蜗中的理解和打击的FBR在CI，这项研究提出调查 炎症因子和淋巴细胞在脑梗死后FBR中的作用。这个项目的长期目标是调查 耳蜗对损伤的免疫反应的根本基础。本研究的目的是确定 CI后炎性FBR中的炎症细胞和淋巴细胞。核心假设是，在耳蜗 （1）巨噬细胞（APC）通过淋巴网络将抗原呈递给淋巴细胞。 （2）淋巴细胞是CI后慢性炎症性FBR所必需的。 通过以下两个目标，我们将测试我们的假设： 1)为了描述CI后耳蜗淋巴引流的病理生理变化，我们将首先建立 耳蜗内注射淋巴示踪剂观察耳蜗淋巴引流至淋巴结盆的方式 淋巴报告小鼠，然后对耳蜗和头颈区域成像。为了研究耳蜗是否 植入导致APC向耳蜗淋巴管的动员增加，我们将进行CI手术 在淋巴报告小鼠中，测定耳蜗神经管中APC的密度，并与 适当的控制。 2)为了确定淋巴细胞是否是炎症和异物反应所必需的， 将在淋巴细胞缺陷小鼠中进行移植，将FBR定量并与 适当的控制。 如果成功，这些目标将增强我们对耳蜗植入后免疫反应的理解。 置入除了耳蜗植入，这些创新将改变目前的耳蜗免疫模式， 反应，并可能导致新的治疗干预无数的内耳病理过程。

Project Summary Cochlear implants (CIs), provides auditory rehabilitation for patients with severe to profound sensorineural hearing loss and can now benefit patients with significant residual low frequency hearing. Implant function and residual hearing can be negatively affected by post-CI inflammatory foreign body response (FBR). While significant body of work has been devoted to probe the role of infiltrating macrophages, the role of lymphocytes has not been thoroughly scrutinized. Moreover, antigen presenting cells (APC e.g., macrophages) are known to mobilize from the end organ to lymph nodes via lymphatic vascular network to present antigen to lymphocytes, activate and recruit lymphocytes. A cochlear lymphatic network has never been described. Using a lymphatic reporter mouse and highly sensitive and specific tracer molecule for lymphatic vessels, we have discovered a rich lymphatic network in cochlea. Besides, in a murine model of CI, we have observed lymphocyte infiltration and activation reinforcing findings in human studies. Given the potential importance of lymphatic anatomy and lymphocytes in the cochlea in understanding and combatting the FBR in CIs, this study proposes to investigate the role lymphatics and lymphocytes in the FBR post-CI. The long-term goal of this project is to investigate fundamental basis of cochlear immune responses to damage. The objective of this study is to determine the role of lymphatics and lymphocytes in the inflammatory FBR post-CI. The central hypothesis is, following cochlear implantation (1) macrophages (APCs) travel through the lymphatic network to present antigens to the lymphocytes and that (2) lymphocytes are necessary for chronic inflammatory FBR post-CI. Undertaking the following two aims, we will test our hypotheses: 1) To characterize the pathophysiological changes in cochlear lymphatic drainage post-CI, we will first establish the pattern of lymphatic drainage of cochlea to lymph node basin by injecting lymphatic tracers into cochlea of lymphatic reporter mice followed by imaging of cochlea and head neck region. To investigate whether cochlear implantation results in increased mobilization of APCs to cochlear lymphatic vessels, we will perform CI surgery in lymphatic reporter mice, determine the density of APCs within cochlear lymphatics, and compare with appropriate controls. 2) To determine whether lymphocytes are necessary for the inflammation and foreign body response, cochlear implantation will be performed in lymphocyte deficient mice, FBR will be quantified and compared with appropriate controls. When successful, these aims will enhance our understanding of the immune response following cochlear implantation. Beyond cochlear implantation, these innovations will shift the current paradigm of cochlear immune response and likely lead to novel therapeutic interventions for a myriad of inner ear pathologic processes.